This proposal delineates a 5-year program to provide the training toward the development of an independent academic research career in the study of neuroimmune interactions that affect energy balance. The goal of this research program will be to determine brain mechanisms that govern dysregulation of energy balance in high-fat diet induced obesity in order to provide molecular targets for therapy. The candidate has been prepared for this pathway by completing MD and PhD degrees and clinical training in Internal Medicine and Endocrinology. This research will be conducted in the laboratory of Dr. Michael Schwartz, an expert in the field of hypothalamic regulation of energy balance and glucose homeostasis, and will involve collaboration with a large group of experts in metabolism and inflammatory biology at the University of Washington. It will be overseen by an expert mentoring committee with several members of the Endocrinology Division as well as three external advisors. The clinical problem of weight gain associated with dietary excess has been hampered by a limited understanding of the central nervous system (CNS) mechanisms that account for this disruption in energy homeostasis. Our preliminary data has uncovered a potential interaction between microglia, the immune cells of the brain, and neurons, the regulators of energy balance. At the onset of high-fat feeding, there is a period of early hyperphagia and a concomitant inflammatory response specifically in the hypothalamus. At the same time, an increase in microglial number and cell size occurs in the arcuate nucleus, a region of the hypothalamus containing leptin-responsive melanocortin (POMC) neurons. Blocking microglial activation results in enhanced susceptibility to high-fat diet-induced weight gain. This research will characterize the mechanisms by which high-fat diet-induced inflammation in the hypothalamus contributes to excess weight gain through two specific aims. In Aim 1, we will examine the energy balance, inflammatory, hormonal, and cellular mechanisms by which microglial inhibition confers increased susceptibility to weight gain on high-fat diets. Aim 2 focuses on the effect of preventing high-fat diet-induced inflammation in the POMC neuron on leptin sensitivity, energy balance, and glucose homeostasis. This research course will provide the training and expertise necessary for an independent investigative career while transitioning the PI toward translational research in the expanding field of neuroimmunology. The overarching goal of this proposal is to determine the mechanisms by which inflammatory signals alter energy homeostasis in order to generate better therapeutic options to improve patient care.